Hematopoiesis is the normal formation of blood cells in the bone marrow. Blood cells develop from pluripotential hematopoietic stem cells (HSCs). The first step in the hematopoietic differentiation process is the commitment of the stem cell to one of two large pathways: myeloid or lymphoid. A myeloid stem cell then matures into a myeloid blast. This blast can form red blood cells, platelets or several types of white blood cells. A lymphoid stem cell matures into a lymphoid blast, which forms into one of several types of white blood cells, such as B cells or T cells. Most blood cells mature in the bone marrow and then move into the blood vessels. Hematopoiesis takes place in a region termed the bone marrow niche. In addition to hematopoietic stem cells, endothelial cells, stromal cells, adipocytes, fibroblasts, and bone cells are found in this niche.
Over the last few years it has become increasingly apparent that several stromal cell types in the bone marrow microenvironment influence the fate of hematopoietic stem cells. These cells include perivascular cells, Nestin-expressing mesenchymal stem cells (MSCs), leptin receptor and SCF-expressing perivascular cells, and endothelial cells (Mendez-Ferrer et al., 2010; Ding et al., 2012; Arai et al., 2004; Lo et al., 2009; Kiel et al., 2005; Sugiyama et al., 2006; Butler et al., 2010; Winkler et al., 2012). The osteoblast, a bone forming cell, is another important determinant of the function of hematopoiesis and the size of the HSC niche (Calvi et al., 2003; Zhang et al., 2003). HSCs within the bone marrow reside preferentially next to the endosteal bone surface suggesting that osteoblasts regulate homing of HSCs (Heissig et al., 2002; Shiozawa et al., 2011). Alterations in osteoblast numbers correlate with changes in the number of long term repopulating HSCs, defects in bone marrow hematopoiesis, and the development of extramedullar hematopoiesis (Visnjic et al., 2004; Calvi et al, 2003; Zhang et al., 2003). Osteoblast progenitors are implicated in HSC mobilization and lineage determination survival and proliferation, initiate ectopic HSC niche formation, and regulate B lymphopoiesis (Mayack and Wagers, 2008; Wu et al., 2008; Zhu et al., 2007; Taichman and Emerson, 1994; Taichman et al, 1996; Chan et al., 2009). The mechanisms through which osteoblasts affect hematopoiesis are now being elucidated and as they emerge, they suggest a variety of signals that can affect different aspects of hematopoiesis. A functional interaction between osteoblasts and HSCs, involving engagement of Notch1/Jag1, signaling promotes HSC proliferation (Calvi et al., 2003; Zhang et al., 2003), whereas inactivation of Wnt signaling in osteoblasts disrupts stem cell quiescence, leading to a loss of self-renewal potential through a Shh-mediated pathway (Schaniel et al., 2011). Recently, disruption of HIF signaling in osteoprogenitors was shown to directly modulate erythropoiesis (Rankin et al., 2012).
Mesenchymal cells, from which osteoblasts originate, have been implicated in the maintenance of leukemia blasts mainly by promoting their localization to the bone marrow. Mouse models of myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS), conditions that in humans predispose one to acute myeloid leukemia (AML), are linked to genetic mutations in both hematopoietic and non-hematopoietic cells (Walkley et al., 2007; Kim et al., 2008). Implicating osteoblasts more directly in this process, is the finding that the disruption of the entire machinery of miRNA formation in osteoblasts resulted in MDS and AML development in mice (Raaijmakers et al., 2010). However, it is not known yet whether a single genetic event taking place in osteoblasts can induce leukemogenesis.
The canonical Wnt signaling pathway is equally important for hematopoiesis and skeletal homeostasis. In hematopoietic stem cells, the pathway affects multineage progenitor differentiation and is a major regulator of bone mass, mainly through its action in osteoblasts. Canonical Wnt signaling acts through β-catenin in early osteochondroprogenitors during skeletogenesis, to induce their differentiation into osteoblasts rather than chondrocytes (Hill et al., 2005; Rodda and McMahon, 2006; Day et al, 2005). β-catenin acts in osteoblasts to inhibit osteoclast formation and suppress bone resorption. This function of β-catenin has no effect on proliferation, differentiation or the bone forming properties of osteoblasts (Glass et al., 2005; Holmen et al., 2005). β-catenin is normally found in the cytoplasm of cells, but mutations may cause it to accumulate in the nucleus. Because of its bone protective properties, canonical Wnt signaling in osteoblasts is currently a major pharmacotherapeutic target.
Abnormal hematopoiesis leads to blood disorders including blood cancers. Every ten minutes, someone in the United States dies from a blood cancer. It was estimated that almost 150,000 people would be diagnosed with leukemia, lymphoma, or myeloma this year, and that an estimated 54,630 deaths from these three diseases combined would occur. Additionally, this year over 48,000 people are expected to be diagnosed with leukemia with almost 24,000 people expected to die of the disease this year. Moreover, leukemia causes about one-third of all cancer deaths in children younger than 15 years (The Leukemia and Lymphoma Society, Facts 2013, pages 1 and 2).
While there are several known treatments for blood cancers, including chemotherapy, radiation, immunotherapy, gene therapy, and stem cell transplantation, there is still a poor prognosis. In patients who are 65 years or older (65 is the median age at diagnosis), survival rates following chemotherapy are in the range of 10%. In younger patients, the survival rate is in the range of 30%, except in the very small fraction of patients. Various modifications of drug delivery and dose have had no significant impact. Additionally, all of these therapies have many unwanted side effects. Chemotherapy can cause extreme fatigue, hair loss, nausea, loss of appetite, and greater risks of infection. Radiation can cause extreme fatigue. Immunotherapy can cause headache, muscle aches, fever, weakness, and anemia. There is a risk of graft-versus-host disease with stem cell transplantation (The Leukemia and Lymphoma Society, Facts 2013, page 2-7). While molecular studies have further refined an understanding of the defects in this disease, none have provided a target for therapy.
Thus, there is a need for the development of additional therapies for leukemia, those without the unwanted, potentially dangerous side effects, as well as a need to identify and early diagnose those who have a blood cancer or disorder.